Ethylbenzene Exposure and Bronchoalveolar CD4/CD8 T Cells in Hypersensitivity Pneumonitis Development and Clinical Outcome

<b>Background:</b> Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by inflammation of the lung parenchyma, alveoli and bronchioles induced by inhalation of organic compounds. Bird-related-HP (BRHP) is the most common type of HP, occurring in susceptible people in regular contact with birds, although a genetic susceptibility is unclear. This study investigates the impact of environmental volatile organic compounds (VOCs) on the development of HP and other pulmonary diseases, and their relationship with pulmonary inflammatory cell composition and patient outcomes. <b>Methods:</b> Geospatial environmental levels of VOCs (benzene, toluene, ethylbenzene, m,p-xylene and o-xylene) in patients' homes were related to bronchoalveolar lavage (BAL) leukocyte profiles analyzed by flow cytometry of 1515 patients with different lung diseases in the region of Murcia (southeastern Spain). <b>Results</b>: Ethylbenzene levels over the threshold limit of 10 µg/m³ (EB10) were associated with HP (23.9% vs. 15.2%, <i>p</i> < 0.05). A strong association with HP was observed in patients in contact with birds living in areas with EB10 (63.0% vs. 27.4%, <i>p</i> < 0.001). Linear regression analysis showed that age (B = -0.058, <i>p</i> < 0.012), smoking (B = -0.125, <i>p</i> < 0.001), bird contact (B = 0.275, <i>p</i> < 0.001) and EB10 (B = 0.109, <i>p</i> < 0.001) were independent variables associated with HP. In HP patients, BAL CD4/CD8-ratio > 1.5 was associated with shorter overall survival (8.9 years vs. not-reached, <i>p</i> < 0.011), probably due to lower CD8+ T-lymphocyte counts observed in HP fibrotic patients (11.65 ± 2.8% vs. 23.6 ± 2.9%, <i>p</i> = 0.008) and in those who died during follow-up (10.0 ± 1.9% vs. 23.8 ± 2.7%, <i>p</i> = 0.012), suggesting a protective role for CD8+ T cells. <b>Conclusions</b>: High environmental ethylbenzene is strongly associated with BRHP. CD8+ T-lymphocytes could have a protective role in HP, preventing fibrosis and increasing overall survival.